Phosphate-binding polymers for oral administration

ABSTRACT

Phosphate-binding polymers are provided for removing phosphate from the gastrointestinal tract. The polymers are orally administered, and are useful for the treatment of hyperphosphatemia.

RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 10/322,904, filedDec. 17, 2002 now U.S. Pat. No. 6,858,203, which is a continuation ofU.S. Ser. No. 09/542,329, filed Apr. 4, 2000, now U.S. Pat. No.6,509,013, which is a continuation of U.S. Ser. No. 08/929,784, filedSep. 15, 1997, now U.S. Pat. No. 6,083,495, which is a divisional ofU.S. Ser. No. 08/471,747, filed Jun. 6, 1995, now U.S. Pat. No.5,667,775, which is a continuation-in-part of U.S. Ser. No. 08/238,458,filed May 5, 1994, now U.S. Pat. No. 5,496,545, which is acontinuation-in-part of U.S. Ser. No. 08/105,591, filed Aug. 11, 1993,now abandoned, the entire teachings of which are incorporated herein byreference.

BACKGROUND OF THE INVENTION

Hyperphosphatemia frequently accompanies diseases associated withinadequate renal function, hypoparathyroidism, and certain other medicalconditions. Hyperphosphatemia is typically defined as possessing a serumphosphate levels of over about 6 mg/dL. The condition, especially ifpresent over extended periods of time, leads to severe abnormalities incalcium and phosphorus metabolism and can be manifested by aberrantcalcification in joints, lungs, and eyes.

Therapeutic efforts to reduce serum phosphate include dialysis,reduction in dietary phosphate, and oral administration of insolublephosphate binders to reduce gastrointestinal absorption. Dialysis andreduced dietary phosphate are generally unsuccessful in adequatelyreversing hyperphosphatemia. Further difficulties in these therapeuticregimens include the invasive nature of dialysis and the difficulties inmodifying dietary habits in the latter therapy.

The oral administration of certain phosphate binders has also beensuggested. Phosphate binders include calcium or aluminum salts. Calciumsalts have been widely used to bind intestinal phosphate and preventabsorption. The ingested calcium combines with phosphate to forminsoluble calcium phosphate salts such as Ca₃(PO₄)₂, CaHPO₄, orCa(H₂PO₄)₂. Different types of calcium salts, including calciumcarbonate, acetate (such as PhosLo® calcium acetate tablets), citrate,alginate, and ketoacid salts have been utilized for phosphate binding.This class of therapeutics generally results in hypercalcemia due fromabsorption of high amounts of ingested calcium. Hypercalcemia has beenindicated in many serious side effects, such as cardiac arrhythmias,renal failure, and skin and visceral calcification. Frequent monitoringof serum calcium levels is required during therapy with calcium-basedphosphate binders.

Aluminum-based phosphate binders, such as Amphojel® aluminum hydroxidegel, have also been used for treating hyperphosphatemia. These compoundscomplex with intestinal phosphate to form highly insoluble aluminumphosphate; the bound phosphate is unavailable for absorption by thepatient. Prolonged use of aluminum gels leads to accumulations ofaluminum, and often to aluminum toxicity, accompanied by such symptomsas encephalopathy, osteomalacia, and myopathy.

Selected ion exchange resins have also been suggested for use in bindingphosphate. Those tested include Dowex® anion-exchange resins in thechloride form, such as XF 43311, XY 40013, XF 43254, XY 40011, and XY40012. These resins have several drawbacks for treatment ofhyperphosphatemia, including poor binding efficiency, necessitating useof high dosages for significant reduction of absorbed phosphate.

Thus a need exists for improved phosphate binders which can beadministered orally in acceptable dosage levels without resulting inmany of the serious side effects discussed above.

SUMMARY OF THE INVENTION

The invention relates to the discovery that a class of anion exchangepolymers have improved phosphate binding properties. In general, theinvention features a method of removing phosphate from a patient by ionexchange, which involves oral administration of a therapeuticallyeffective amount of a composition containing at least onephosphate-binding polymer. The polymers of the invention may becrosslinked with a crosslinking agent.

The invention provides an effective treatment for decreasing the serumlevel of phosphate by binding phosphate in the gastrointestinal tract,without comcomittantly increasing the absorption of any clinicallyundesirable materials, particularly calcium or aluminum.

Other features and advantages will be apparent from the followingdescription of the preferred embodiments and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of the bound phosphate relevant to solutionphosphate concentration after a phosphate solution is treated withpoly(dimethylaminopropyl-acrylamide).

FIG. 2 is a graphic illustration of the phosphate concentration in fecalsamples taken from rats fed with a dietary supplement of a crosslinkedpolyallylamine and micro-crystalline cellulose (placebo).

FIG. 3 is a graphic illustration of the urinary phosphate concentrationin rats similarly given a dietary supplement of a crosslinkedpolyallylamine and micro-crystalline cellulose (placebo).

DETAILED DESCRIPTION OF THE INVENTION

A description of preferred embodiments of the invention follows.

The polymers of the invention generally include hydrophilic anionexchange resins, particularly aliphatic amine polymers. The “amine”group can be present in the form of a primary, secondary or tertiaryamine, quaternary ammonium salt, amidine, guanadine, hydrazine, orcombinations thereof. The amine can be within the linear structure ofthe polymer (such as in polyethylenimine or a condensation polymer of apolyaminoalkane, e.g. diethylenetriamine, and a crosslinking agent, suchas epichlorohydrin) or as a functional group pendant from the polymerbackbone (such as in polyallylamine, polyvinylamine orpoly(aminoethyl)acrylate).

In one aspect, the polymer is characterized by a repeating unit havingthe formula

or a copolymer thereof, wherein n is an integer and each R,independently, is H or a substituted or unsubstituted alkyl, such as alower alkyl (e.g., having between 1 and 5 carbon atoms, inclusive),alkylamino (e.g., having between 1 and 5 carbons atoms, inclusive, suchas ethylamino) or aryl (e.g., phenyl) group.

In a second aspect, the polymer is characterized by a repeating unithaving the formula

or a copolymer thereof, wherein n is an integer, each R, independently,is H or a substituted or unsubstituted alkyl (e.g., having between 1 and5 carbon atoms, inclusive), alkylamino (e.g., having between 1 and 5carbons atoms, inclusive, such as ethylamino) or aryl (e.g., phenyl)group, and each X⁻ an exchangeable negatively charged counterion.

One example of a copolymer according to the second aspect of theinvention is characterized by a first repeating unit having the formula

wherein n is an integer, each R, independently, is H or a substituted orunsubstituted alkyl (e.g., having between 1 and 5 carbon atoms,inclusive), alkylamino (e.g., having between 1 and 5 carbons atoms,inclusive, such as ethylamino) or aryl group (e.g., phenyl), and each X⁻is an exchangeable negatively charged counterion; and furthercharacterized by a second repeating unit having the formula

wherein each n, independently, is an integer and each R, independently,is H or a substituted or unsubstituted alkyl (e.g., having between 1 and5 carbon atoms, inclusive), alkylamino (e.g., having between 1 and 5carbons atoms, inclusive, such as ethylamino) or aryl group (e.g.,phenyl).

In a fourth aspect, the polymer is characterized by a repeating unithaving the formula

or a copolymer thereof, wherein n is an integer, and R is H or asubstituted or unsubstituted alkyl (e.g., having between 1 and 5 carbonatoms, inclusive), alkylamino (e.g., having between 1 and 5 carbonsatoms, inclusive, such as ethylamino) or aryl group (e.g., phenyl).

One example of a copolymer according to the second aspect of theinvention is characterized by a first repeating unit having the formula

wherein n is an integer, and R is H or a substituted or unsubstitutedalkyl (e.g., having between 1 and 5 carbon atoms, inclusive), alkylamino(e.g., having between 1 and 5 carbons atoms, inclusive, such asethylamino) or aryl group (e.g., phenyl); and further characterized by asecond repeating unit having the formula

wherein each n, independently, is an integer and R is H or a substitutedor unsubstituted alkyl (e.g., having between 1 and 5 carbon atoms,inclusive), alkylamino (e.g., having between 1 and 5 carbon atoms,inclusive, such as ethylamino) or aryl group (e.g., phenyl).

In a fifth aspect, the polymer is characterized by a repeating grouphaving the formula

or a copolymer thereof, wherein n is an integer, and each R₁ and R₂,independently, is H or a substituted or unsubstituted alkyl (e.g.,having between 1 and 5 carbon atoms, inclusive), and alkylamino (e.g.,having between 1 and 5 carbons atoms, inclusive, such as ethylamino) oraryl group (e.g., phenyl), and each X⁻ is an exchangeable negativelycharged counterion.

In one preferred polymer according to the fifth aspect of the invention,at least one of the R groups is a hydrogen atom.

In a sixth aspect, the polymer is characterized by a repeat unit havingthe formula

or a copolymer thereof, where n is an integer, each R₁ and R₂,independently, is H, a substituted or unsubstituted alkyl groupcontaining 1 to 20 carbon atoms, an alkylamino group (e.g., havingbetween 1 and 5 carbons atoms, inclusive, such as ethylamino), or anaryl group containing 6 to 12 atoms (e.g., phenyl).

In a seventh aspect, the polymer is characterized by a repeat unithaving the formula

or a copolymer thereof, wherein n is an integer, each R₁, R₂ and R₃,independently, is H, a substituted or unsubstituted alkyl groupcontaining 1 to 20 carbon atoms, an alkylamino group (e.g., havingbetween 1 and 5 carbons atoms, inclusive, such as ethylamino), or anaryl group containing 6 to 12 atoms (e.g., phenyl), and each X⁻ is anexchangeable negatively charged counterion.

In each case, the R groups can carry one or more substituents. Suitablesubstituents include therapeutic anionic groups, e.g., quaternaryammonium groups, or amine groups, e.g., primary and secondary alkyl oraryl amines. Examples of other suitable substituents include hydroxy,alkoxy, carboxamide, sulfonamide, halogen, alkyl, aryl, hydrazine,guanadine, urea, and carboxylic acid esters, for example.

The polymers are preferably crosslinked, in some cases by adding acrosslinking agent to the reaction mixture during or afterpolymerization. Examples of suitable crosslinking agents are diacrylatesand dimethacrylates (e.g., ethylene glycol diacrylate, propylene glycoldiacrylate, butylene glycol diacrylate, ethylene glycol dimethacrylate,propylene glycol dimethacrylate, butylene glycol dimethacrylate,polyethyleneglycol dimethacrylate, polyethyleneglycol diacrylate),methylene bisacrylamide, methylene bismethacrylamide, ethylenebisacrylamide, epichlorohydrin, epibromohydrin, toluene diisocyanate,ethylenebismethacrylamide, ethylidene bisacrylamide, divinyl benzene,bisphenol A dimethacrylate, bisphenol A diacrylate, 1,4butanedioldiglycidyl ether, 1,2 ethanedioldiglycidyl ether,1,3-dichloropropane, 1,2-dichloroethane, 1,3-dibromopropane,1,2-dibromoethane, succinyl dichloride, dimethylsuccinate, acryloylchloride, or pyromellitic dianhydride.

The amount of crosslinking agent is typically between about 0.5 andabout 75 weight %, and preferably between about 1 and about 25% byweight, based upon the combined weight of crosslinking and monomer. Inanother embodiment, the crosslinking agent is present between about 2and about 20% by weight of polymer.

In some cases the polymers are crosslinked after polymerization. Onemethod of obtaining such crosslinking involves reaction of the polymerwith difunctional crosslinkers, such as epichlorohydrin, succinyldichloride, the diglycidyl ether of bisphenol A, pyromelliticdianhydride, toluence diisocyanate, and ethylenediamine. A typicalexample is the reaction of poly(ethyleneimine) with epichlorohydrin. Inthis example the epichlorohydrin (1 to 100 parts) is added to a solutioncontaining polyethyleneimine (100 parts) and heated to promote reaction.Other methods of inducing crosslinking on already polymerized materialsinclude, but are not limited to, exposure to ionizing radiation,ultraviolet radiation, electron beams, radicals, and pyrolysis.

Examples of preferred crosslinking agents include epichlorohydrin, 1,4butanedioldiglycidyl ether, 1,2 ethanedioldiglycidyl ether,1,3-dichloropropane, 1,2-dichloroethane, 1,3-dibromopropane,1,2-dibromoethane, succinyl dichloride, dimethylsuccinate, toluenediisocyanate, acryloyl chloride, and pyromellitic dianhydride.

The negatively charged counterions, X⁻, can be organic ions, inorganicions, or a combination thereof. The inorganic ions suitable for use inthis invention include halide (especially chloride), carbonate,bicarbonate, sulfate, bisulfate, hydroxide, nitrate, persulfate andsulfite. Suitable organic ions include acetate, ascorbate, benzoate,citrate, dihydrogen citrate, hydrogen citrate, oxalate, succinate,tartrate, taurocholate, glycocholate, and cholate.

In a preferred embodiment, the counterion does not have a detrimentalside effect to the patient but rather is selected to have a therapeuticor nutritional benefit to the patient.

EXAMPLES

Candidate polymers were tested by stirring them in a phosphatecontaining solution at pH 7 for 3 hours. The solution was designed tomimic the conditions present in the small intestine.

Solution Contents 10–20 mM Phosphate   80 mM Sodium Chloride   30 mMSodium Carbonate

The pH was adjusted to pH 7, once at the start of the test and again atthe end of the test, using either aqueous NaOH or HCl. After 3 hours thepolymer was filtered off and the residual phosphate concentration in thetest solution was determined spectrophotometrically. The differencebetween the initial phosphate concentration and the final concentrationwas used to determine the amount of phosphate bound to the polymer. Thisresult is expressed in milliequivalents per gram of starting polymer(meq/g).

Table 1 below shows the results obtained for several polymers. Highernumbers indicate a more effective polymer.

TABLE 1 Phosphate Bound Polymer (meq/g)*Poly(allylamine/epichlorohydrin) 3.1 Poly(allylamine/butanedioldiglycidyl ether) 2.7 Poly(allylamine/ethanediol diglycidyl ether) 2.3Poly(allyltrimethylammonium chloride) 0.3 Poly(ethyleneimine)/acryloylchloride 1.2 Polethyleneimine “C” 2.7 Polyethyleneimine “A” 2.2Poly(DET/EPI) 1.5 Polyethyleneimine “B” 1.2Poly(dimethylaminopropylacrylamide) 0.8 Poly(PEH/EPI) 0.7Poly(trimethylammoniomethyl styrene chloride) 0.7Poly(pentaethylenehexaminemethacrylamide) 0.7Poly(tetraethylenepentaminemethacrylamide) 0.7Poly(diethylenetriaminemethacrylamide) 0.5Poly(triethylenetetraminemethacrylamide) 0.5Poly(aminoethylmethacrylamide) 0.4 Poly(vinylamine) 0.4 Poly(MAPTAC)0.24 Poly(methylmethacrylate/PEI) 0.2 Poly(dimethylethyleneiminechloride) 0.2 Poly(diethylaminopropylmethacrylamide) 0.1Poly(guanidinoacrylamide) 0.1 Poly(guanidinobutylacrylamide) 0.1Poly(guanidinobutylmethacrylamide) 0.1 *The values apply when theresidual solution phosphate levels are ~5 mM.

Table 2 shows results obtained using various other materials to bindphosphate.

TABLE 2 Phosphate Bound Polymer (meq/g)* Calcium Chloride 4.0 CalciumLactate 2.4 Ox-Absorb ® 0.5 Maalox Plus ® 0.3 Sephadex DEAE A-25, 40–125m 0.2 Aluminum Hydroxide, Dried Gel 0.2 *The values apply when theresidual solution phosphate levels are ~5 mM.

Table 3 shows results obtained for a variety of salts made frompolyethyleneimine and organic and inorganic acids.

TABLE 3 Phosphate Bound Polymer (meq/g)* Poly(ethyleneimine sulfate A)0.9 Poly(ethyleneimine sulfate B) 1.2 Poly(ethyleneimine sulfate C) 1.1Poly(ethyleneimine sulfate D) 1.7 Poly(ethyleneimine tartrate A) 0.7Poly(ethyleneimine tartrate B) 0.9 Poly(ethyleneimine tartrate C) 1.1Poly(ethyleneimine ascorbate A) 0.55 Poly(ethyleneimine ascorbate B)0.65 Poly(ethyleneimine ascorbate C) 0.9 Poly(ethyleneimine citrate A)0.7 Poly(ethyleneimine citrate B) 1.0 Poly(ethyleneimine citrate C) 0.9Poly(ethyleneimine succinate A) 1.1 Poly(ethyleneimine succinate B) 1.3Poly(ethyleneimine chloride) 1.1 *The values apply when the residualsolution phosphate levels are ~5 mM.

Oxabsorb® is an organic polymer that encapsulates calcium such that thecalcium is available to bind to such ions as phosphate, but may not bereleased by the polymer and thus is not supposed to be absorbed by thepatient.

The amount of phosphate bound by all of these materials, both polymersand inorganic gels, is expected to vary as the phosphate concentrationvaries. The graph FIG. 1 below shows the relationship between thesolution phosphate concentration and the amount of phosphate bound topoly(dimethylaminopropylacrylamide). Other polymers of the class areexpected to show a similar relationship.

In an alternate type of test, the polymer was exposed to an acidicenvironment prior to exposure to phosphate as might happen in apatient's stomach. The solid (0.1 g) was suspended in 40 mL of 0.1 MNaCl. This mixture was stirred for 10 minutes, and the pH was adjustedto 3.0 with 1 M HCl, and the mixture was stirred for 30 minutes. Themixture was centrifuged, the supernatant decanted, and the solidresuspended in 40 mL of 0.1 m NaCl. This mixture was stirred for 10minutes, the pH was adjusted to 3.0 with 1 M HCl, and the mixture wasstirred for 30 minutes. The mixture was centrifuged, the supernatantdecanted, and the solid residue used in the usual phosphate assay.Results are shown in Table 4 for a variety of polymers and for aluminumhydroxide dried gel. In most cases the values for the amount ofphosphate bound are higher in this test than in the usual assay.

TABLE 4 Phosphate Bound Polymer (meq/g)* Poly(ethyleneimine sulfate B)1.2 Poly(ethyleneimine sulfate C) 1.3 Poly(ethyleneimine tartrate B) 1.3Poly(ethyleneimine tartrate C) 1.4 Poly(ethyleneimine ascorbate B) 1.0Poly(ethyleneimine ascorbate C) 1.0 Poly(ethyleneimine citrate B) 1.0Poly(ethyleneimine citrate C) 1.3 Poly(ethyleneimine succinate A) 1.1Poly(ethyleneimine succinate B) 1.3 Poly(ethyleneimine chloride) 1.4Aluminum Hydroxide 0.7 *The values apply when the residual solutionphosphate levels are ~5 mM.Rat Dietary Phosphorus Excretion Model

Six 6–8 week old Sprague-Dawley rats were placed in metabolic cages andfed semi-purified rodent chow powder containing 0.28% inorganicphosphorus. The diets were supplemented with 1.7%poly(allylamine/epichlorohydrin) or micro-crystalline cellulose; theanimals served as their own controls by receiving cellulose orpoly(allylamine/epichlorohydrin) in randomized order. The rats were fedad libitum for three days to acclimate to the diet. Feces excretedduring the next 48 hours were collected, lyophilized, and ground intopowder. The inorganic phosphate content was determined according to themethod of Taussky and Shorr: Microdetermination of Inorganic Phosphate.One gram of powdered feces was burned to remove carbon, then ashed in a600° C. oven. Concentrated HCl was then added to dissolve thephosphorus. The phosphorus was determined with ferrous sulfate-ammoniummolybdate reagent. Intensity of the blue color was determined at 700 nmon a Perkin-Elmer spectrophotometer through a 1 cm cell.

The results are shown in FIG. 2. Fecal phosphate concentration increasedin all animals.

Urinary Phosphate Excretion in Partially Nephrectomized Rats

Sprague-Dawley rats, approximately 8 weeks old, were 75% nephrectomized.One kidney was surgically removed; approximately 50% of the renal arteryflow to the contralateral kidney was ligated. The animals were fed asemi-purified rodent chow containing 0.385% inorganic phosphorus andeither 10% poly(allylamine/epichlorohydrin) or cellulose. Urine wascollected and analyzed for phosphate content on specific days. Absorbeddietary phosphate is excreted into the urine to maintain serumphosphate.

The results are shown in FIG. 3. None of the animals becamehyperphosphatemic or uremic, indicating that the residual kidneyfunction was adequate to filter the absorbed phosphate load. The animalsreceiving the poly(allylamine/epichlorohydrin) demonstrated a trendtowards reduced phosphate excretion, indicative of reduced phosphateabsorption.

Syntheses

Poly(allylamine hydrochloride)—To a 5 L, water jacketed reaction kettleequipped with 1) a condenser topped with a nitrogen gas inlet and 2) athermometer and 3) a mechanical stirrer was added concentratedhydrochloric acid (2590 mL). The acid was cooled to 5° C. usingcirculating water in the jacket of the reaction kettle at 0° C.Allylamine (2362 mL; 1798 g) was added dropwise with stirring,maintaining a temperature of 5–10° C. After the addition was complete,1338 mL of liquid was removed by vacuum distillation at 60–70° C.Azobis(amidinopropane) dihydrochloride (36 g) suspended in 81 mL waterwas added. The kettle was heated to 50° C. under a nitrogen atmospherewith stirring for 24 hours. Azobis(amidinopropane) dihydrochloride (36g) suspended in 81 mL water was again added and the heating and stirringcontinued for an additional 44 hours. Distilled water (720 mL) was addedand the solution allowed to cool with stirring. The liquid was addeddropwise to a stirring solution of methanol (30 L). The solid was thenremoved by filtration, resuspended in methanol (30 L), stirred 1 hour,and collected by filtration. This methanol rinse was repeated once moreand the solid was dried in a vacuum oven to yield 2691 g of a granularwhite solid (poly(allylamine hydrochloride).Poly(allylamine/epichlorohydrin)—To a 5 gallon bucket was addedpoly(allylamine hydrochloride) (2.5 kg) and water 10 L). The mixture wasstirred to dissolve and the pH was adjusted to 10 with a solid NaOH. Thesolution was allowed to cool to room temperature in the bucket andepichlorohydrin (250 mL) was added all at once with stirring. Themixture was stirred gently until it gelled after about 15 minutes. Thegel was allowed to continue curing for 18 hours at room temperature. Thegel was then removed and put into a blender with isopropanol (about 7.5L). The gel was mixed in the blender with about 500 mL isopropanol for˜3 minutes to form coarse particles and the solid was then collected byfiltration. The solid was rinsed three times by suspending it in 9gallons of water, stirring the mixture for 1 hour, and collecting thesolid by filtration. The solid was rinsed once by suspending it inisopropanol (60 L), stirring the mixture for 1 hour, and collecting thesolid by filtration. The solid was dried in a vacuum oven for 18 hoursto yield 1.55 Kg of a granular, brittle, white solid.Poly(allylamine/butanedioldiglycidyl ether)—To a 5 gallon plastic bucketwas added poly(allylamine hydrochloride) (500 g) and water (2 L). Themixture was stirred to dissolve and the pH was adjusted to 10 with solidNaOH (142.3 g). The solution was allowed to cool to room temperature inthe bucket and 1,4-butanedioldiglycidyl ether (130 mL) was added all atonce with stirring. The mixture was stirred gently until it gelled after4 minutes. The gel was allowed to continue curing for 18 hours at roomtemperature. The gel was then removed and dried in a vacuum oven at 75°C. for 24 hours. The dry solid was ground and sieved for −30 mesh andthen suspended in 6 gallons on water. After stirring for 1 hour thesolid was filtered off and rinse process repeated twice more. The solidwas rinsed twice in isopropanol (3 gallons), and dried in a vacuum ovenat 50° C. for 24 hours to yield 580 g of a white solid.Poly(allylamine/ethanedioldiglycidyl ether)—To a 100 mL beaker was addedpoly(allylamine hydrochloride) (10 g) and water (40 mL). The mixture wasstirred to dissolve and the pH was adjusted to 10 with solid NaOH. Thesolution was allowed to cool to room temperature in the beaker and 1,2ethanedioldiglycidyl ether (2.0 mL) was added all at once with stirring.The mixture was allowed to continue curing for 18 hours at roomtemperature. The gel was then removed and blended in 500 mL of methanol.The solid was filtered off and suspended in water (500 mL). Afterstirring for 1 hour the solid was filtered off and the rising processrepeated. The solid was rinsed twice in isopropanol (400 mL), and driedin a vacuum oven at 50° C. for 24 hours to yield 8.7 g of a white solid.Poly(allylamine/dimethylsuccinate)—To a 500 mL round bottom flask wasadded poly(allylamine hydrochloride) (10 g), methanol (100 mL), andtriethylamine (10 mL). The mixture was stirred and dimethylsuccinate (1mL) was added. The solution was heated to reflux and stirring turned offafter 30 minutes. After 18 hours the solution was cooled to roomtemperature and solid was filtered off and suspended in water (1 L).After stirring for 1 hour the solid was filtered off and the rinseprocess repeated twice more. The solid was rinsed once in isopropanol(800 mL), and dried in a vacuum oven at 50° C. for 24 hours to yield 5.9g of a white solid.Poly(allyltrimethylammonium chloride)—To a 500 mL three necked flaskequipped with a magnetic stirrer, a thermometer, and a condenser toppedwith a nitrogen inlet, was added poly(allylamine) crosslinked withepichlorohydrin (5.0 g), methanol (300 mL), methyl iodide (20 mL), andsodium carbonate (50 g). The mixture was then cooled and water was addedto total volume of 2 L. Concentrated hydrochloric acid was added untilno further bubbling resulted and the remaining solid was filtered off.The solid was rinsed twice in 10% aqueous NaCl (1 L) by stirring for 1hour followed by filtration to recover the solid. The solid was thenrinsed three times by suspending it in water (2 L), stirring for 1 hour,and filtering to recover the solid. Finally, the solid was rinsed asabove in methanol and dried in a vacuum over at 50° C. for 18 hours toyield 7.7 g of white granular solid.Poly(ethyleneimine)/acryloyl chloride—Into a 5 L three neck flaskequipped with a mechanical stirrer, a thermometer, and an additionalfunnel was added polyethyleneimine (510 g of a 50% aqueous solution(equivalent to 255 g of dry polymer) and isopropanol (2.5 L). Acryloylchloride (50 g) was added dropwise through the addition funnel over a 35minute period, keeping the temperature below 29° C. The solution wasthen heated to 60° C. with stirring for 18 hours. The solution wascooled and solid immediately filtered off. The solid was rinsed threetimes by suspending it in water (2 gallons), stirring for 1 hour, andfiltering to recover the solid. The solid was rinsed once by suspendingit in methanol (2 gallons), stirring for 30 minutes, and filtering torecover the solid. Finally, the solid was rinsed as above in isopropanoland dried in a vacuum over at 50° C. for 18 hours to yield 206 g oflight orange granular solid.

Poly(dimethylaminopropylacrylamide)—Dimethylamino-propylacrylamide (10g) and methylene-bisacrylamide (1.1 g) were dissolved in 50 mL of waterin a 100 mL three neck flask. The solution was stirred under nitrogenfor 10 minutes. Potassium persulfate (0.3 g) and sodium metabisulfite(0.3 g) were each dissolved in 2–3 mL of water and then mixed. After afew seconds this solution was added to the monomer solution, still undernitrogen. A gel formed immediately and was allowed to sit overnight. Thegel was removed and blended with 500 mL of isopropanol. The solid wasfiltered off and rinsed three times with acetone. The solid white powderwas filtered off and dried in a vacuum oven to yield 6.1 g.

Poly(Methacrylamidopropyltrimethylammoniumchloride)=[Poly(MAPTAC)]—[3-(Methacryloylamino)propyl]trimethylammonium chloride (38 mLof 50% aqueous solution) and methylenebis-methacrylamide (2.2 g) werestirred in a beaker at room temperature. Methanol (10 mL was added andthe solution was warmed to 40° C. to fully dissolve the bisacrylamide.Potassium persulfate (0.4 g) was added and the solution stirred for 2minutes. Potassium metabisulfite (0.4 g) was added and stirring wascontinued. After 5 minutes the solution was put under a nitrogenatmosphere. After 20 minutes the solution contained significantprecipitate and the solution was allowed to sit overnight. The solid waswashed three times with isopropanol and collected by filtration. Thesolid was then suspended in water 500 (mL) and stirred for several hoursbefore being collected by centrifugation. The solid was again washedwith water and collected by filtration. The solid was then dried in avacuum oven to yield 21.96 g.

Poly(ethyleneimine) “A”—Polyethyleneimine (50 g of a 50% aqueoussolution; Scientific Polymer Products) was dissolved in water (100 mL).Epichlorohydrin (4.6 mL) was added dropwise. The solution was heated to55° C. for 4 hours, after which it had gelled. The gel was removed,blended with water (1 L) and the solid was filtered off. It wasresuspended in water (2 L) and stirred for 10 minutes. The solid wasfiltered off, the rinse repeated once with water and twice withisopropanol, and the resulting gel was dried in a vacuum oven to yield26.3 g of a rubbery solid.Poly(ethyleneimine) “B” and Poly(ethyleneimine) “C” were made in asimilar manner, except using 9.2 and 2.3 mL of epichlorohydrin,respectively.Poly(methylmethacrylate-co-divinylbenzene)—Methylmeth-acrylate (50 g)and divinylbenzene (5 g) and azobisiso-butyronitrile (1.0 g) weredissolved in isopropanol (500 mL) and heated to reflux for 18 hoursunder a nitrogen 14 atmosphere. The solid white precipitate was filteredoff, rinsed once in acetone (collected by centrifugation), once in water(collected by filtration and dried in a vacuum oven to yield 19.4 g.

Poly(diethylenetriaminemethacrylamide)—Poly(methyl-methacrylate-co-divinylbenzene)(20 g) was suspended in diethylenetriamine (200 mL) and heated to refluxunder a nitrogen atmosphere for 18 hours. The solid was collected byfiltration, resuspended in water (500 mL), stirred 30 minutes, filteredoff, resuspended in water (500 mL), stirred 30 minutes, filtered off,rinsed briefly in isopropanol, and dried in a vacuum oven to yield 18.0g.

Poly(pentaethylenehexaminemethacrylamide),Poly(tetraethylenepentamine-methacrylamide), andPoly(triethylenetetraaminemethacrylamide) were made in a manner similarto poly(diethylenetriaminemethacrylamide) from pentaethylenehexamine,tetraethylenepentamine, and triethylenetetraamine, respectively.Poly(methylmethacrylate/PEI)—Poly(methylmethacrylate-co-divinylbenzene)(1.0 g) was added to a mixture containing hexanol (9150 mL) andpolyethyleneimine (15 g in 15 g water). The mixture was heated to refluxunder nitrogen for 4 days. The reaction was cooled and the solid wasfiltered off, suspended in methanol (300 mL), stirred 1 hour, andfiltered off. The rinse was repeated once with isopropanol and the solidwas dried in a vacuum oven to yield 0.71 g.

Poly(aminoethylmethacrylamide)—Poly(methylmethacrylate-co-divinylbenzene)(20 g) was suspended in ethylenediamine 9200 mL) and heated to refluxunder a nitrogen atmosphere for 3 days. The solid was collected bycentrifugation, washed by resuspending it in water (500 mL), stirringfor 30 minutes, and filtering off the solid. The solid was washed twicemore in water, once in isopropanol, and dried in a vacuum oven to yield17.3 g.

Poly(diethylaminopropylmethacrylamide)—Poly(methyl-methacrylate-co-divinylbenzene)(20 g) was suspended in diethylaminopropylamine (200 mL) and heated toreflux under a nitrogen atmosphere for 18 hours. The solid was collectedby filtration, resuspended in water (500 mL), filtered off, resuspendedin water (500 mL), collected by filtration, rinsed briefly inisopropanol, and dried in a vacuum oven to yield 8.2 g.

NHS-acrylate—N-Hydroxysuccinimide (NHS, 157.5 g) was dissolved inchloroform (2300 mL) in a 5 L flask. The solution was cooled to 0° C.and acryloyl chloride (132 g) was added dropwise, keeping thetemperature 2° C. After addition was complete, the solution was stirredfor 1.5 hours, rinsed with water (1100 mL) in a separatory funnel anddried over anhydrous sodium sulfate. The solvent was removed undervacuum and a small amount of ethyl acetate was added to the residue.This mixture was poured into hexane (200 mL) with stirring. The solutionwas heated to reflux, adding more ethyl acetate (400 mL). The insolubleNHS was filtered off, hexane (1 L) was added, the solution was heated toreflux, ethyl acetate (400 mL) was added, and the solution allowed tocool to <10° C. The solid was then filtered off and dried in a vacuumoven to yield 125.9 g. A second crop of 80 g was subsequently collectedby further cooling.

Poly(NHS-acrylate)—NHS-acrylate (28.5 g), methylenebis-acrylamide (1.5g) and tetrahydrofuran (500 mL) were mixed in a 1 L flask and heated to50° C. under a nitrogen atmosphere. Azobisisobutyronitrile (0.2 g) wasadded, the solution was stirred for 1 hour, filtered to remove excessN-hydroxysuccinimide, and heated to 50° C. for 4.5 hours under anitrogen atmosphere. The solution was then cooled and the solid wasfiltered off, rinsed in tetrahydrofuran, and dried in a vacuum oven toyield 16.1 g.

Poly(guanidinobutylacrylamide)—Poly(NHS-acrylate) (1.5 g) was suspendedin water (25 mL) containing agmatine (1.5 g) which had been adjusted topH 9 with solid NaOH. The solution was stirred for 4 days, after whichtime the pH had dropped to 6.3. Water was added to a total of 500 mL,the solution was stirred for 30 minutes and the solid was filtered off.The solid was rinsed twice in water, twice in isopropanol, and dried ina vacuum oven to yield 0.45 g.

Poly(methacryloyl chloride)—Methacryloyl chloride (20 mL), divinylbenzene (4 mL of 80% purity), AIBN (0.4 g), and THF (150 mL) werestirred at 60° C. under a nitrogen atmosphere for 18 hours. The solutionwas cooled and the solid was filtered off, rinsed in THF, then acetone,and dried in a vacuum oven to yield 8.1 g.

Poly(guanidinobutylmethacrylamide)—Poly(methacryloyl chloride) (0.5 g),agmatine sulfate (1.0 g), triethylamine (2.5 mL), and acetone (50 mL)were stirred together for 4 days. Water (100 mL) was added and themixture stirred for 6 hours. The solid was filtered off and washed byresuspending in water (500 mL), stirring for 30 minutes, and filteringoff the solid. The wash was repeated twice in water, once in methanol,and the solid was dried in a vacuum oven to yield 0.41 g.

Poly(guanidinoacrylamide)—The procedure forpoly-(guanidinobutylacrylamide) was followed substituting aminoguanidinebicarbonate (5.0 g) for the agmatine, yielding 0.75 g.Poly(PEH/EPI)—Epichlorohydrin (1.5 g) was added dropwise to a solutioncontaining pentaethylenehexamine (20 g) and water (100 mL), keeping thetemperature between 65° C. The solution was stirred until it gelled andheating was continued for 4 hours (at 65° C.). After sitting overnightat room temperature the gel was removed and blended with water (1 L).The solid was filtered off, water was added (1 L), and the blending andfiltration were repeated. The gel was suspended in isopropanol and theresulting solid was collected by filtration and dried in a vacuum ovento yield 28.2 g.

Ethylidenebisacetamide—Acetamide (118 g), acetaldehyde (44.06 g), copperacetate (0.2 g), and water (300 mL) were placed in a 1 L three neckflask fitted with condenser, thermometer, and mechanical stirred.Concentrated HCl (34 mL) was added and the mixture was heated to 45–50°C. with stirring for 24 hours. The water was then removed in vacuo toleave a thick sludge which formed crystals on cooling to 5° C. Acetone(200 mL) was added and stirred for a few minutes after which the solidwas filtered off and discarded. The acetone was cooled to 0° C. andsolid was filtered off. This solid was rinsed in 500 mL acetone and airdried 18 hours to yield 31.5 g.

Vinylacetamide—Ethylidenebisacetamide (31.05), calcium carbonate (2 g)and celite 541 (2 g) were placed in a 500 mL three neck flask fittedwith a thermometer, a mechanical stirrer, and a distilling head atop avigroux column. The mixture was vacuum distilled at 35 mm Hg by heatingthe pot to 180–225° C. Only a single fraction was collected (10.8 g)which contained a large portion of acetamide in addition to the product(determined by NMR). This solid product was dissolved in isopropanol (30mL) to form the crude solution used for polymerization.

Poly(vinylacetamide)—Crude vinylacetamide solution (15 mL),divinylbenzene (1 g, technical grade, 55% pure, mixed isomers), and AIBN(0.3 g) were mixed and heated to reflux under a nitrogen atmosphere for90 minutes, forming a solid precipitate. The solution was cooled,isopropanol (50 mL) was added, and the solid was collected bycentrifugation. The solid was rinsed twice in isopropanol, once inwater, and dried in a vacuum oven to yield 0.8 g.

Poly(vinylamine)—Poly(vinylacetamide) (0.79 g) was placed in a 100 mLone neck flask containing water 25 mL and concentrated HCl 25 mL. Themixture was refluxed for 5 days, the solid was filtered off, rinsed oncein water, twice in isopropanol, and dried in a vacuum oven to yield 0.77g. The product of this reaction (˜0.84 g) was suspended in NaOH (46 g)and water (46 g) and heated to boiling (˜140° C.). Due to foaming thetemperature was reduced and maintained at ˜100° C. for 2 hours. Water(100 mL) was added and the solid collected by filtration. After rinsingonce in water the solid was suspended in water (500 mL) and adjusted topH 5 with acetic acid. The solid was again filtered off, rinsed withwater, then the isopropanol, and dried in a vacuum oven to yield 0.51 g.Poly(trimethylammoniomethylstyrene chloride) is the copolymer oftrimethylammoniomethylstyrene chloride and divinyl benzene.Poly(DET/EPI) is the polymer formed by reaction of diethylenetriamineand epichlorohydrin.Poly(ethyleneimine) Salts—Polyethyleneimine (25 g dissolved in 25 gwater) was dissolved in water (100 mL) and mixed with toluene (1 L).Epichlorohydrin (2.3 mL) was added and the mixture heated to 60° C. withvigorous mechanical stirring for 18 hours. The mixture was cooled andthe solid filtered off, resuspended in methanol (2 L), stirred 1 hour,and collected by centrifugation. The solid was suspended in water (2 L),stirred 1 hour, filtered off, suspended in water (4 L), stirred 1 hour,and again filtered off. The solid was suspended in acetone (4 L) andstirred 15 minutes, the liquid was poured off, acetone (2 L) was added,the mixture was stirred 15 minutes, the acetone was again poured off,and the solid was dried in a vacuum oven to form intermediate “D”.Poly(ethyleneimine sulfate A)—Intermediate “D” (1.0 g) was suspended inwater (150 mL), stirred 30 minutes, and partially neutralized withsulfuric acid (1.1 g). The mixture was stirred an additional 30 minutes,the solid was filtered off, resuspended in methanol (200 mL), stirred 5minutes, filtered off, and dried in a vacuum oven.Poly(ethyleneimine sulfate B)—Intermediate “D” (1.0 g) was suspended inwater (150 mL), stirred 30 minutes, and partially neutralized withsulfuric acid (0.57 g). The mixture was stirred an additional 30minutes, the solid was filtered off, resuspended in methanol (200 mL),stirred 5 minutes, filtered off, and dried in a vacuum oven.Poly(ethyleneimine sulfate C)—Intermediate “D” (1.0 g) was suspended inwater (150 mL), stirred 30 minutes, and partially neutralized withsulfuric acid (0.28 g). The mixture was stirred an additional 30minutes, the solid was filtered off, resuspended in methanol (200 mL),stirred 5 minutes, filtered off, and dried in a vacuum oven.Poly(ethyleneimine sulfate D)—Intermediate “D” (1.0 g) was suspended inwater (150 mL), stirred 30 minutes, and partially neutralized withsulfuric acid (0.11 g). The mixture was stirred an additional 30minutes, the solid was filtered off, resuspended in methanol (200 mL),stirred 5 minutes, filtered off, and dried in a vacuum oven.Poly(ethyleneimine tartrate A)—Intermediate “D” (1.0 g) was suspended inwater (150 mL), stirred 30 minutes, and partially neutralized withtartaric acid (1.72 g). The mixture was stirred an additional 30minutes, the solid was filtered off, resuspended in methanol (200 mL),stirred 5 minutes, filtered off, and dried in a vacuum oven.Poly(ethyleneimine tartrate B)—Intermediate “D” (1.0 g) was suspended inwater (150 mL), stirred 30 minutes, and partially neutralized withtartaric acid (0.86 g). The mixture was stirred an additional 30minutes, the solid was filtered off, resuspended in methanol (200 mL),stirred 5 minutes, filtered off, and dried in a vacuum oven.Poly(ethyleneimine tartrate C)—Intermediate “D” (1.0 g) was suspended inwater (150 mL), stirred 30 minutes, and partially neutralized withtartaric acid (0.43 g). The mixture was stirred an additional 30minutes, the solid was filtered off, resuspended in methanol (200 mL),stirred 5 minutes, filtered off, and dried in a vacuum oven.Poly(ethyleneimine ascorbate A)—Intermediate “D” (1.0 g) was suspendedin water (150 mL), stirred 30 minutes, and partially neutralized withascorbic acid (4.05 g). The mixture was stirred an additional 30minutes, the solid was filtered off, resuspended in methanol (200 mL),stirred 5 minutes, filtered off, and dried in a vacuum oven.Poly(ethyleneimine ascorbate B)—Intermediate “D” (1.0 g) was suspendedin water (150 mL), stirred 30 minutes, and partially neutralized withascorbic acid (2.02 g). The mixture was stirred an additional 30minutes, the solid was filtered off, resuspended in methanol (200 mL),stirred 5 minutes, filtered off, and dried in a vacuum oven.Poly(ethyleneimine ascorbate C)—Intermediate “D” (1.0 g) was suspendedin water (150 mL), stirred 30 minutes, and partially neutralized withascorbic acid (1.01 g). The mixture was stirred an additional 30minutes, the solid was filtered off, resuspended in methanol (200 mL),stirred 5 minutes, filtered off, and dried in a vacuum oven.Poly(ethyleneimine citrate A)—Intermediate “D” (1.0 g) was suspended inwater (150 mL), stirred 30 minutes, and partially neutralized withcitric acid (1.47 g). The mixture was stirred an additional 30 minutes,the solid was filtered off, resuspended in methanol (200 mL), stirred 5minutes, filtered off, and dried in a vacuum oven.Poly(ethyleneimine citrate B)—Intermediate “D” (1.0 g) was suspended inwater (150 mL), stirred 30 minutes, and partially neutralized withcitric acid (0.74 g). The mixture was stirred an additional 30 minutes,the solid was filtered off, resuspended in methanol (200 mL), stirred 5minutes, filtered off, and dried in a vacuum oven.Poly(ethyleneimine citrate C)—Intermediate “D” (1.0 g) was suspended inwater (150 mL), stirred 30 minutes, and partially neutralized withcitric acid (0.37 g). The mixture was stirred an additional 30 minutes,the solid was filtered off, resuspended in methanol (200 mL), stirred 5minutes, filtered off, and dried in a vacuum oven.Poly(ethyleneimine succinate A)—Intermediate “D” (1.0 g) was suspendedin water (150 mL), stirred 30 minutes, and partially neutralized withsuccinic acid (1.36 g). The mixture was stirred an additional 30minutes, the solid was filtered off, resuspended in methanol (200 mL),stirred 5 minutes, filtered off, and dried in a vacuum oven.Poly(ethyleneimine succinate B)—Intermediate “D” (1.0 g) was suspendedin water (150 mL), stirred 30 minutes, and partially neutralized withsuccinic acid (0.68 g). The mixture was stirred an additional 30minutes, the solid was filtered off, resuspended in methanol (200 mL),stirred 5 minutes, filtered off, and dried in a vacuum oven.Poly(ethyleneimine chloride)—Polyethyleneimine (100 g in 100 g water)was dissolved in water (640 mL additional) and the pH was adjusted to 10with concentrated HCl. Isopropanol (1.6 L) was added, followed byepichlorohydrin (19.2 mL). The mixture was stirred under nitrogen for 18hours at 60° C. The solids were filtered off and rinsed with methanol(300 mL) on the funnel. The solid was rinsed by resuspending it inmethanol (4 L), stirring 30 minutes, and filtering off the solid. Therinse was repeated twice with methanol, followed by resuspension inwater (1 gallon). The pH was adjusted to 1.0 with concentrated HCl, thesolid was filtered off, resuspended in water (1 gallon), the pH againadjusted to 1.0 with concentrated HCl, the mixture stirred 30 minutes,and the solid filtered off. The methanol rinse was again repeated andthe solid dried in a vacuum oven to yield 112.4 g.Poly(dimethylethyleneimine chloride)—Poly(ethyleneimine chloride) (5.0g) was suspended in methanol (300 mL) and sodium carbonate (50 g) wasadded. Methyl iodide (20 mL) was added and the mixture heated to refluxfor 3 days. Water was added to reach a total volume of 500 mL, themixture stirred for 15 minutes, and the solid filtered off. The solidwas suspended in water (500 mL), stirred 30 minutes, and filtered. Thesolid was suspended in water (1 L), the pH adjusted to 7.0 withconcentrated HCl, and the mixture stirred for 10 minutes. The solid wasfiltered off, resuspended in isopropanol (1 L), stirred 30 minutes,filtered off, and dried in a vacuum oven to yield 6.33 g.Use

The methods of the invention involve treatment of patients withhyperphosphatemia. Elevated serum phosphate is commonly present inpatients with renal insufficiency, hypoparathyroidism,pseudohypoparathyroidism, acute untreated acromegaly, overmedicationwith phosphate salts, and acute tissue destruction as occurs duringrhabdomyolysis and treatment of malignancies.

The term “patient” used herein is taken to mean any mammalian patient towhich phosphate binders may be administered. Patients specificallyintended for treatment with the methods of the invention include humans,as well as nonhuman primates, sheep, horses, cattle, goats, pigs, dogs,cats, rabbits, guinea pigs, hamsters, gerbils, rats and mice.

The compositions utilized in the methods of the inventions are orallyadministered in therapeutically effective amounts. Further, the polymerare preferably non-toxic and stable upon administration. Atherapeutically effective amount of compound is that amount whichproduces a result or exerts an influence on the particular conditionbeing treated. As used herein, a therapeutically effective amount of aphosphate binder means an amount which is effective in decreasing theserum phosphate levels of the patient to which it is administered.

By “non-toxic” it is meant that when ingested in therapeuticallyeffective amounts neither the polymers nor any ions released into thebody upon ion exchange are harmful or are substantially harmful.

By “stable” it is meant that when ingested in therapeutically effectiveamounts the polymers do not dissolve or otherwise decompose to formpotentially harmful by-products, and remain substantially intact so thatthey can transport bound phosphate out of the body.

The present pharmaceutical compositions are generally prepared by knownprocedures using well known and readily available ingredients. In makingthe compositions of the present invention, the polymeric phosphatebinder may be present alone, may be admixed with a carrier, diluted by acarrier, or enclosed within a carrier which may be in the form of acapsule, sachet, paper or other container. When the carrier serves as adiluent, it may be a solid, semi-solid or liquid material which acts asa vehicle, excipient or medium for the polymer. Thus, the compositionscan be in the form of tablets, pills, powders, lozenges, sachets,cachets, elixirs, suspensions, syrups, aerosols, (as a solid or in aliquid medium), soft or hard gelatin capsules, sterile packaged powders,and the like. Examples of suitable carrier, excipients, and diluentsinclude foods, drinks, lactose, dextrose, sucrose, sorbitol, mannitol,starches, gum acacia, alginates, tragacanth, gelatin, calcium silicate,microcrystalline cellulose, polyvinylpyrrolidone, cellulose, methylcellulose, methylhydroxybenzoates, propylhydroxybenzoates,propylhydroxybenzoates, and talc.

It should be understood, however, that the foregoing description of theinvention is intended merely to be illustrative by way of example onlyand than other modifications, embodiments, and equivalents may beapparent to those skilled in the art without departing from its spirit.

1. A pharmaceutical composition comprising a carrier and a crosslinked,water insoluble polyallylamine homopolymer, wherein said polyallylaminehomopolymer comprises repeat units represented by the structuralformula:

wherein n is an integer, wherein said polyallylamine homopolymer iscrosslinked with an epichlorohydrin crosslinking agent, and wherein thehomopolymer is fully protonated, partially protonated or unprotonated.2. The pharmaceutical composition of claim 1, wherein the amount of saidcrosslinking agent is about 2% to about 20% by weight of the polymer. 3.The pharmaceutical composition of claim 1, wherein said polyallylaminehomopolymer is fully or partially protonated.
 4. The pharmaceuticalcomposition of claim 3, wherein said polyallylamine homopolymer isprotonated with HCl.
 5. The pharmaceutical composition of claim 4,wherein said polyallylamine homopolymer is partially protonated.
 6. Thepharmaceutical composition of claim 1, wherein said pharmaceuticalcomposition consists essentially of one or more carriers and saidpolyallylamine homopolymer.
 7. The pharmaceutical composition of claim1, wherein said pharmaceutical composition consists of one or morecarriers and said polyallylamine homopolymer.
 8. The pharmaceuticalcomposition at claim 1, wherein said pharmaceutical composition is inthe form of a tablet or a capsule.
 9. A method for removing phosphatefrom a patient, comprising orally administering to said patient atherapeutically effective amount of a composition comprising acrosslinked, water insoluble polyallylamine homopolymer, wherein saidpolyallylamine homopolymer comprises repeat units represented by thestructural formula:

wherein n is an integer, and wherein the homopolymer is fullyprotonated, partially protonated or unprotonated.
 10. The method ofclaim 9, wherein said polyallylamine homopolymer is crosslinked with anepichlorohydrin crosslinking agent.
 11. The method of claim 10, whereinthe amount of said crosslinking agent is about 2% to about 20% by weightof the polymer.
 12. The method of claim 9, wherein said polyallylaminehomopolymer is fully or partially protonated.
 13. The method of claim12, wherein said polyallylamine homopolymer is protonated with HCl. 14.The method of claim 13, wherein said polyallylamine homopolymer ispartially protonated.